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Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists

Nature Genetics volume 42, pages 608–613 (2010)Cite this article

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Abstract

Platelet function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in this process. We tested association of 2.5 million SNPs with platelet aggregation responses to three agonists (ADP, epinephrine and collagen) in two cohorts of European ancestry (N ≤ 2,753 in the Framingham Heart Study, N ≤ 1,238 in the Genetic Study of Atherosclerosis Risk). We identified associations of seven loci with platelet aggregation near or within GP6 (P = 4.6 × 10−13), PEAR1 (P = 3.4 × 10−12), ADRA2A (P = 3.3 × 10−11), PIK3CG (P = 3.1 × 10−9), JMJD1C (P = 1.6 × 10−8), MRVI1 (P = 2.0 × 10−8) and SHH (P = 4.5 × 10−8). Six of these loci replicated at P < 0.05 in an additional African-American cohort (N ≤ 840 in the Genetic Study of Atherosclerosis Risk). These results provide insights into platelet aggregation pathways and may suggest new antiplatelet therapeutic targets.

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Figure 1: Genome-wide association meta-analysis plots for ADP-induced platelet aggregation response after filtering of SNPs for quality control.
Figure 2: Genome-wide association meta-analysis plots for epinephrine-induced platelet aggregation response after filtering of SNPs for QC.

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References

  1. Wolff, T., Miller, T. & Ko, S. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann. Intern. Med. 150, 405–410 (2009).

    Article  Google Scholar 

  2. Quinn, M.J. & Topol, E.J. Common variations in platelet glycoproteins: pharmacogenomic implications. Pharmacogenomics 2, 341–352 (2001).

    Article  CAS  Google Scholar 

  3. Faraday, N., Becker, D.M. & Becker, L.C. Pharmacogenomics of platelet responsiveness to aspirin. Pharmacogenomics 8, 1413–1425 (2007).

    Article  CAS  Google Scholar 

  4. O'Donnell, C.J. et al. Genetic and environmental contributions to platelet aggregation: the Framingham Heart Study. Circulation 103, 3051–3056 (2001).

    Article  CAS  Google Scholar 

  5. Bray, P.F. et al. Heritability of platelet function in families with premature coronary artery disease. J. Thromb. Haemost. 5, 1617–1623 (2007).

    Article  CAS  Google Scholar 

  6. Salles, I.I. et al. Inherited traits affecting platelet function. Blood Rev. 22, 155–172 (2008).

    Article  CAS  Google Scholar 

  7. Yang, Q., Kathiresan, S., Lin, J.P., Tofler, G.H. & O'Donnell, C.J. Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Med. Genet. 8, S12 (2007).

    Article  Google Scholar 

  8. Herrera-Galeano, J.E. et al. A novel variant in the platelet endothelial aggregation receptor-1 gene is associated with increased platelet aggregability. Arterioscler. Thromb. Vasc. Biol. 28, 1484–1490 (2008).

    Article  CAS  Google Scholar 

  9. Jones, C.I., et al. & on behalf of the Bloodomics consortium A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways. Blood 114, 1405–1416 (2009).

    Article  CAS  Google Scholar 

  10. Freeman, K. et al. Genetic polymorphism of the α2-adrenergic receptor is associated with increased platelet aggregation, baroreceptor sensitivity, and salt excretion in normotensive humans. Am. J. Hypertens. 8, 863–869 (1995).

    Article  CAS  Google Scholar 

  11. Kambayashi, J. et al. Prevalence of impaired responsiveness to epinephrine in platelets among Japanese. Thromb. Res. 81, 85–90 (1996).

    Article  CAS  Google Scholar 

  12. Croft, S.A. et al. Novel platelet membrane glycoprotein VI dimorphism is a risk factor for myocardial infarction. Circulation 104, 1459–1463 (2001).

    Article  CAS  Google Scholar 

  13. Joutsi-Korhonen, L. et al. The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression. Blood 101, 4372–4379 (2003).

    Article  CAS  Google Scholar 

  14. Nanda, N. et al. Platelet endothelial aggregation receptor 1 (PEAR1), a novel epidermal growth factor repeat-containing transmembrane receptor, participates in platelet contact-induced activation. J. Biol. Chem. 280, 24680–24689 (2005).

    Article  CAS  Google Scholar 

  15. Yabe, M. et al. Identification of ADRA2A polymorphisms related to shear-mediated platelet function. Biochem. Biophys. Res. Commun. 347, 1001–1005 (2006).

    Article  CAS  Google Scholar 

  16. Small, K.M., Brown, K.M., Seman, C.A., Theiss, C.T. & Liggett, S.B. Complex haplotypes derived from noncoding polymorphisms of the intronless α2A-adrenergic gene diversify receptor expression. Proc. Natl. Acad. Sci. USA 103, 5472–5477 (2006).

    Article  CAS  Google Scholar 

  17. Trifiro, E. et al. The low-frequency isoform of platelet glycoprotein VIb attenuates ligand-mediated signal transduction but not receptor expression or ligand binding. Blood 114, 1893–1899 (2009).

    Article  CAS  Google Scholar 

  18. Massberg, S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J. Exp. Med. 197, 41–49 (2003).

    Article  CAS  Google Scholar 

  19. Bezemer, I.D. et al. Gene variants associated with deep vein thrombosis. J. Am. Med. Assoc. 299, 1306–1314 (2008).

    Article  CAS  Google Scholar 

  20. Tregouet, D.A. et al. Common susceptibility allele are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 113, 5298–5303 (2009).

    Article  CAS  Google Scholar 

  21. Schlossmann, J. et al. Regulation of intracellular calcium by a signaling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 404, 197–201 (2000).

    Article  CAS  Google Scholar 

  22. Antl, M. et al. IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation. Blood 109, 552–559 (2007).

    Article  CAS  Google Scholar 

  23. Martínez, M.C. et al. Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens. Blood 108, 3012–3020 (2006).

    Article  Google Scholar 

  24. Soranzo, N. et al. A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function. Blood 113, 3831–3837 (2009).

    Article  CAS  Google Scholar 

  25. Schoenwaelder, S.M. et al. Identification of a unique co-operative phosphoinositide 3-kinase signaling mechanism regulating integrin αIIbβ3 adhesive function in platelets. J. Biol. Chem. 282, 28648–28658 (2007).

    Article  CAS  Google Scholar 

  26. Yowe, D. et al. RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signaling molecule highly expressed in megakaryocytes. Biochem. J. 359, 109–118 (2001).

    Article  CAS  Google Scholar 

  27. Gagnon, A.W., Murray, D.L. & Leadley, R.J. Cloning and characterization of a novel regulator of G protein signaling in human platelets. Cell. Signal. 14, 595–606 (2002).

    Article  CAS  Google Scholar 

  28. Kim, S.D. et al. The expression patterns of RGS transcripts in platelets. Platelets 17, 493–497 (2006).

    Article  CAS  Google Scholar 

  29. García, A. et al. Differential proteome analysis of TRAP-activated platelets: involvement of DOK-2 and phosphorylation of RGS proteins. Blood 103, 2088–2095 (2004).

    Article  Google Scholar 

  30. Guidetti, G.F. et al. The Gi-coupled P2Y12 receptor regulates diacylglycerol-mediated signaling in human platelets. J. Biol. Chem. 283, 28795–28805 (2008).

    Article  CAS  Google Scholar 

  31. Cannobbio, I. et al. Genetic evidence for a predominant role of PI3Kβ catalytic activity in ITAM- and integrin-mediated signaling in platelets. Blood 114, 2193–2196 (2009).

    Article  Google Scholar 

  32. Wang, Z. et al. Rap1b is critical for glycoprotein VI-mediated but not ADP receptor-mediated α2β1 activation. J. Thromb. Haemost. 7, 693–700 (2009).

    Article  CAS  Google Scholar 

  33. Chrzanowska-Wodnicka, M. et al. Rap1b is required for normal platelet function and hemostasis in mice. J. Clin. Invest. 115, 680–687 (2005).

    Article  CAS  Google Scholar 

  34. Letschka, T. et al. PKC-θ selectivity controls the adhesion-stimulating molecule Rap1. Blood 112, 4617–4627 (2008).

    Article  CAS  Google Scholar 

  35. Severson, E.A., Lee, W.Y., Capaldo, C.T., Nusrat, A. & Parkos, C.A. Junctional adhesion molecule A interacts with Afadin and PDZ-GEF2 to activate Rap1a, regulate β1 integrin levels, and enhance cell migration. Mol. Biol. Cell 20, 1916–1925 (2009).

    Article  CAS  Google Scholar 

  36. Ellies, L.G. et al. Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands. Proc. Natl. Acad. Sci. USA 99, 10042–10047 (2002).

    Article  CAS  Google Scholar 

  37. Grewal, P.K. et al. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat. Med. 14, 648–655 (2008).

    Article  CAS  Google Scholar 

  38. Holada, K., Glierova, H., Simak, J. & Vostal, J.G. Expression of cellular prion protein on platelets from patients with gray platelet or Hermansky-Pudlak syndrome and the protein's association with α-granules. Haematologica 91, 1126–1129 (2006).

    CAS  PubMed  Google Scholar 

  39. Jones, M. et al. Human platelets as a substrate source for the in vitro amplification of the abnormal prion protein (PrPSc) associated with variant Creutzfeldt-Jakob disease. Transfusion 49, 376–384 (2009).

    Article  CAS  Google Scholar 

  40. Meisinger, C. et al. A genome-wide association study identifies three loci associated with mean platelet volume. Am. J. Hum. Genet. 84, 66–71 (2009).

    Article  CAS  Google Scholar 

  41. Johnson, A.D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  Google Scholar 

  42. Shaughnessy, J.D. et al. Mrvil, a common MRV integration site in BXH2 myeloid leukemias, encodes a protein with homology to a lymphoid-restricted membrane protein Jaw1. Oncogene 18, 2069–2084 (1999).

    Article  CAS  Google Scholar 

  43. Watkins, N.A. et al. A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 113, e1–e9 (2009).

    Article  CAS  Google Scholar 

  44. Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am. J. Epidemiol. 110, 281–290 (1979).

    Article  CAS  Google Scholar 

  45. Mukamal, K.J. et al. Alcohol consumption and platelet activation and aggregation among women and men: The Framingham Offspring Study. Alcohol. Clin. Exp. Res. 29, 1906–1912 (2005).

    Article  CAS  Google Scholar 

  46. Becker, D.M. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. J. Am. Med. Assoc. 295, 1420–1427 (2006).

    Article  CAS  Google Scholar 

  47. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  48. Chen, M.H. & Yang, Q. GWAF: an R package for genome-wide association analysis with family data. Bioinformatics 26, 580–581 (2010).

    Article  Google Scholar 

  49. Littell, R.C., Milliken, G.A., Stroup, W.W. & Wolfinger, R.D. SAS System for Mixed Models. (SAS Institute, Cary, North Carolina, 1996).

    Google Scholar 

Download references

Acknowledgements

This work was supported by the US National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This work was supported by the National Heart, Lung, and Blood Institute through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia, and through R01-HL-48157. This research was conducted in part using the resources of the Johns Hopkins General Clinical Research Center, funded through the National Center for Research Resources, M01-RR000052 and the Washington University DSG cluster. We thank G. Ehret and S. Ganesh for providing R code that was modified to generate plots displayed in Figures 1 and 2 and Supplementary Figure 2.

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Author notes

  1. Christopher J O'Donnell and Lewis C Becker: These authors contributed equally to this work.

Authors and Affiliations

  1. National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, Massachusetts, USA

    Andrew D Johnson, Ming-Huei Chen, Martin G Larson, Qiong Yang & Christopher J O'Donnell

  2. Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA

    Andrew D Johnson & Christopher J O'Donnell

  3. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Lisa R Yanek, Diane M Becker & Lewis C Becker

  4. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA

    Ming-Huei Chen

  5. Department of Anesthesia and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nauder Faraday

  6. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA

    Martin G Larson

  7. Royal North Shore Hospital, University of Sydney, Sydney, Australia

    Geoffrey Tofler

  8. Division of Statistical Genomics, Washington University of Medicine, St. Louis, Missouri, USA

    Shiow J Lin, Aldi T Kraja & Michael A Province

  9. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA

    Qiong Yang

  10. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Christopher J O'Donnell

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Contributions

A.D.J., L.R.Y., C.J.O. and L.C.B. led the study. A.D.J. took primary responsibility for drafting the manuscript with contributions and editing from L.R.Y., M.-H.C., N.F., M.G.L., G.T., A.T.K., Q.Y., D.M.B., C.J.O. and L.C.B. G.T., M.G.L. and C.J.O. were involved in the original guidance, collection and analysis of Framingham platelet phenotype data. L.R.Y., N.F., D.M.B. and L.C.B. were involved in the guidance, collection and analysis for the Genetic Study of Atherosclerosis Risk (GeneStar) phenotype data. S.J.L., A.T.K. and M.A.P. designed the database and analysis system used in GeneStar analyses. A.D.J., L.R.Y. and M.-H.C. conducted genome-wide association analyses. A.D.J., L.R.Y., M.-H.C. and A.T.K. conducted additional analyses on SNP replication and the percent of variance explained. M.-H.C. conducted the meta-analyses. All authors read and approved the final version of the manuscript.

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Correspondence to Andrew D Johnson.

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Johnson, A., Yanek, L., Chen, MH. et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet 42, 608–613 (2010). https://doi.org/10.1038/ng.604

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